Using a preparation that was in limited supply, we previously assessed Interferon-alpha 1 (IFN-alpha 1) clinically in a randomized, double blind comparison to IFN-alpha 2. The frequency of side effects was much less with IFN-alpha1 (p less than 0,01). Yet effects of IFN-alpha 1 on granulocyte counts, NK cell cytotoxicity, and an ISG were comparable to IFN-alpha2. These findings suggest that IFN-alpha 1 might be given with better tolerance and or higher doses than IFN-alpha 2. Recombinant DNA produced IFN-alpha 1 has now come available in adequate supply through a collaboration with the Ministry of Public Health in Shanghai. In randomized, multi-center clinical trials in China, IFN-alpha 1 has proven effective for chronic hepatitis B and C. Data from China also suggests IFN-alpha 1 is better tolerated than IFN-alpha 2. IFN-alpha 1, together with IFN-alpha 2, is a predominant IFN-alpha species generally characteristic of an IFN. However, IFN-alpha 1 has differing receptor binding affinities and differing cross species antiviral activity differences in the transcription factor complexes activated in response to IFN-alpha 1 as compared to IFN-alpha 2. In addition to expected IFN antiproliferative and gene stimulatory (ISG) effects, we have also identified an increase in STAT1 protein expression and induction of apoptosis in myeloma cells by IFN-alpha 1. Studies of IFN-alpha have been designed with the following goals: a) confirm good clinical tolerance and define the dose response characteristics of ISG induction in patients, b) compare the signal transducing and gene modulatory activity to those of IFN-alpha 2 by oligonucleotide gene array and assessment of transcription activating factors, c) study apoptosis and gene induction in myeloma and renal carcinoma to confirm clinical antitumor activity. Since expanded clinical use of IFN- alpha 2 has increasingly been limited by side effects, IFN-alpha 1 may be particularly important in extending clinical leads provided by LFN-alpha 2. Finally, results will further confirm the postulate that antiviral specific activity in vitro does not predict for other biological and clinical effects of IFN. In addition, if the pattern of novel gene induction and cellular effects are expanded, IFN-alpha 1 could have a broader spectrum of responsive clinical tumor types.